The IRCSSA will investigate mechanisms underlying stress, self-control and addictive behaviors. The development of addictive, or compulsive behaviors, is hypothesized to involve a combination of loss of inhibitory (self) control over behavior and enhanced motivation for rewards. A wealth of data has shown profound effects of stress on virtually all aspects of addictive behavior and our data suggest that chronic stress can facilitate the development of habitual or compulsive responses. We hypothesize that stress promotes the transition from goal-directed to habitual behavioral patterns through effects governed by both striatal and prefrontal cortical (RFC) brain structures. The expression of addictive behavior is also associated with increases in the motivational impact of reward-associated cues, effects thought to be mediated by the nucleus accumbens (NAc) [unreadable] a critical site for the motivational aspects of both natural and drug rewards. Both the RFC and the NAc receive afferent dopaminergic input from the ventral tegmental area (VTA), and the RFC receives and noradrenergic inputs from the locus coeruleus (LC), and these projections are activated both by stress and addictive drugs. Stress also increases levels of corticotrophinreleasing- factor (CRF), a neuropeptide with an important role in integrating responses to stress. Since both the VTA and LC express CRF receptors, stress-induced increases in CRF in these regions may provide a link by which stress can influence the cognitive-motivational processes underlying addictive behavior. Aim 1 will test the hypothesis that chronic stress produces cognitive deficits and motivational alterations associated with compulsive behavior in experimental animals by concurrently reducing inhibitory control and enhancing the motivational impact of reward-associated cues, thereby promoting the development of instrumental habits. Aim 2 will use selective RNAi-based approaches to determine the role of VTA and LC CRF receptors in the effects of stress on these food-motivated behaviors. Aim 3 will explore stress-induced changes in gene expression in the LC and VTA. Together, these studies will complement the imaging studies on stressinduced alterations in cortico-limbic-striatal function and behavioral/cellular studies on endocannabinoids and catecholaminergic signaling in RFC pyramidal neurons and PFC-striatal circuits, as well as projects on cueinduced craving and self-control/decision making in human and animal models. Findings from these studies will elucidate brain mechanisms underlying stress induced compulsive behaviors that can then lead to new drug development and therapies for preventing and decreasing compulsive behaviors such as addictions.